Traditionally, synthetic chiral bioactive compounds were used in racemic form, since technology for resolving isomers was either unavailable, or impractical for use on a commercial scale. However, the bioactive component of such a racemate is typically found in only one of two or more of isomeric forms, meaning that at least half of the administered compound does not provide the intended benefit. It is also known that the opposite enantiomer of an intended drug can have a completely different therapeutic action. In some instances, the presence of the opposite enantiomer can be toxic. The biologically inactive isomers are, nonetheless, typically as bioavailable as the active isomer, and thus provide sources of risk without an offsetting benefit. Accordingly, regulators prefer some significant level of isomeric purity. See, e.g. FDA's Policy Statement for the Development of New Stereoisomeric Drugs (May 1, 1992). Technologies for resolving compounds have improved, allowing manufacturers to more readily conform to this regulatory pressure. Nonetheless, the art needs additional isomer resolution techniques that are adaptable to commercial scale and are cost effective.
Classical techniques for resolving optical isomers have included preferential precipitation/crystallization of a chiral compound that is associated with, covalently or non-covalently, an auxiliary chiral resolving compound or moiety. Advances in chromatography techniques effective to resolve isomers have helped provide analytical tools, but such techniques are of somewhat limited industrial applicability due to the associated cost. Dynamic resolution techniques are available, such as methods that react a chiral compound that is covalently attached to an auxiliary chiral resolving compound, or methods that utilize an enolization and Schiff base formation to convert isomeric forms.
The invention provides a new, cost effective technique that resolves the isomeric mixture while increasing the amount of the desired isomer. The technique avoids the formation of intermediate covalent adducts with auxiliary chiral resolving moieties, where such covalent bonds can be difficult to reverse without destroying desired chemical moieties. Such intermediate adducts are particularly difficult to remove in the context of the alpha-substituted carboxylic acids used in the dynamic resolution technique described here, as the leaving groups of the alpha substitution are not well preserved in the adduct removal chemistries. The technique of the invention uses partially insoluble salts of the alpha-substituted carboxylic acids formed with chiral amine compounds, yet unexpectedly the amine moieties do not disrupt the chemistry of the dynamic resolution technique.